Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=O.C[N:19]([CH:21]=O)C.[C-:23]#[N:24].[Na+].CN>O>[C:23]([C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:13]([NH:19][CH3:21])=[O:15])#[N:24]
Reactant: [C-]#N
Reactant: CCOC(=O)c1cnn(-c2ccccc2)c1Cl
Reactant: CN(C)C=O
Agent: CN
Agent: [Na+]
Solvent: O
Product: CNC(=O)c1cnn(-c2ccccc2)c1C#N
Temperature: 25 °C

Procedure:
A 250 ml round bottom flask fitted with a mechanical stirrer was charged with 25.0 g (0.1 mol) of 92.33% pure 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid, ethyl ester and 60 ml of DMF. The mixture was stirred at room temperature for a short period and then 9.8 g (0.2 mol) of sodium cyanide was added. The resulting dark mixture was heated at approximately 100° C. for 6 hours and cooled to room temperature. The reaction mixture was stirred for approximately 12 hours at this temperature and then charged with 27.13 g (0.35 mol) of an aqueous solution of 40% methylamine by weight (hereinafter 40% aqueous methylamine, from Aldrich Chemical Co., Milwaukee Wis.). The reaction mixture was stirred for approximately 61/2 hours and 60 ml of water was added. The resulting suspension was stirred for approximately 10 minutes and the precipitated solid was collected by filtration. The solid was washed with water and vacuum dried to provide 18.36 g of 5-cyano-1-phenyl-N-methyl-1H-pyrazole-4-carboxamide. A high pressure liquid chromatographic analysis of the final product indicated it to be 97.86% pure. Corrected yield 86.1%. m/e 226.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([O:14]CC)=O)[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1.[CH3:22][NH:23][CH3:24]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([N:23]([CH3:24])[CH3:22])=[O:14])[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1
Reactant: CNC
Reactant: CCOC(=O)Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)N(C)C)C1
Temperature: 120 °C

Procedure:
A mixture of ethyl 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate (100 mg) and dimethylamine (1 ml) was heated at 120° C. for 15 h to obtain 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-N,N-dimethylacetamide after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.
Reaction SMILES: C1CC[CH:4]([N:7]=[C:8]=NC2CCCCC2)CC1.Br[CH2:17]/[CH:18]=[CH:19]/[C:20]([OH:22])=O.[C:23]([C:25]1[CH:26]=[C:27]([NH:31][C:32]2[C:33]3[CH:41]=[C:40]([NH2:42])[N:39]=[CH:38][C:34]=3[N:35]=[CH:36][N:37]=2)[CH:28]=[CH:29][CH:30]=1)#[CH:24].C(N(C(C)C)CC)(C)C.CNC.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.CC(N(C)C)=O>[CH3:4][N:7]([CH3:8])[CH2:17]/[CH:18]=[CH:19]/[C:20]([NH:42][C:40]1[N:39]=[CH:38][C:34]2[N:35]=[CH:36][N:37]=[C:32]([NH:31][C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([C:23]#[CH:24])[CH:26]=3)[C:33]=2[CH:41]=1)=[O:22]
Reactant: O=C(O)/C=C/CBr
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C#Cc1cccc(Nc2ncnc3cnc(N)cc23)c1
Agent: CNC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: C#Cc1cccc(Nc2ncnc3cnc(NC(=O)/C=C/CN(C)C)cc23)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 50.9 %

Procedure:
To a solution of DCC (7.23 g, 35.1 mmol) in dry THF (25 ml) at 0° C. under nitrogen, was added solid acid 9 (5.79 g, 35.1 mmol). The reaction mixture was stirred at 0° C. for 35 min before solid aniline 169 (1.83 g, 7.01 mmol) was added, followed by dry DMA (20 mL) and di-iso-propylethylamine (DIPEA) (6.11 ml, 35.1 mmol). The final reaction mixture was stirred at 0° C. for 45 min before being cooled to −15 to −20° C. (bath). 40% Aqueous dimethylamine (10.6 mL, 84.0 mmol) was then added and after 25 min the reaction mixture was poured into cold 2% aqueous sodium carbonate (200 mL) and the product was extracted into ethyl acetate (600 mL), which was washed successively with water (300 mL), cold 2% aqueous sodium carbonate (300 mL) and water (300 mL). The ethyl acetate solution was dried (Na2SO4) and evaporated under reduced pressure to give a solid which was purified by column chromatography on silica gel eluting with DCM/MeOH (gradient from 100:0 to 15:1), to give (2E)-4-(dimethylamino)-N-[4-(3-ethynylanilino)pyrido[3,4-d]pyrimidin-6-yl]-2-butenamide (171) (1.33 g, 51%) as a yellow/orange solid, mp 163-166° C. 1H NMR δ [(CD3)2SO] 10.89 (s, 1H), 10.25 (s, 1H), 9.02 (s, 1H), 9.00 (s, 1H), 8.63 (s, 1H), 8.02 (br s, 1H), 7.94-7.87 (m, 1H), 7.42 (t, J=7.9 Hz, 1H), 7.26 (br d, J=7.7 Hz, 1H), 6.88 (dt, J=15.4, 6.0 Hz, 1H), 6.52 (br d; J=15.4 Hz, 1H), 4.19 (s, 1H), 3.09 (dd, J=6.0, 1.2 Hz, 2H), 2.19 (s, 6H). Anal. Calcd for C21H20N6O.0.2H2O: C, 67.08; H, 5.47; N, 22.35%. Found C, 66.88; H, 5.47; N, 22.22%.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=O)=[CH:4][CH:3]=1.C(OP([CH2:21][C:22](=[O:27])[NH:23][CH:24]1[CH2:26][CH2:25]1)(=O)OCC)C>>[CH:24]1([NH:23][C:22](=[O:27])/[CH:21]=[C:9]2\[CH2:8][CH2:7][CH2:6][C:5]3[C:10]\2=[CH:11][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:26][CH2:25]1
Reactant: O=C1CCCc2ccc(F)cc21
Reactant: CCOP(=O)(CC(=O)NC1CC1)OCC
Product: O=C(/C=C1\CCCc2ccc(F)cc21)NC1CC1
Yield: 35.7 %

Procedure:
This compound was prepared in an analogous manner to Example 12f with the replacement of 5-fluoro1-tetralone and diethyl (cyclopropylcarbamoyl)methyl phosphonate with 7-fluoro-1-tetralone (7.76 g, 0.05 mol) and diethyl(cyclo propylcarbamoyl)methylphosphonate (11.1 g, 0.05 mol). Chromatography on Silica gel using ethyl acetate:hexanes (1:2) as eluent gave 4.38 g (37%) of (E)-N-Cyclopropyl-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene) acetamide, m.p., 122.8°-123.3° C.; NMR (DMSO-d6): d 8.00 (d, J=4.0 Hz,1H), 7.32 (dd, J=11.2 Hz,1H), 7.04-7.23 (m, 2H), 6.33 (s, 1H), 3.06 (m,2H), 2.69 (m, 3H), 1.70 (m, 2H), 0.66 (m, 2H), 0.40 (m, 2H); steady-state nOe: irradiation at 6.39 d, observed significant nOe at 7.32 d.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]([C:19]([F:22])([F:21])[F:20])[O:8][C:9]2[C:15]([CH:16]=[CH2:17])=[CH:14][C:13]([Cl:18])=[CH:12][C:10]=2[CH:11]=1)=[O:5])=C.[OH-].[Na+]>C1COCC1.C(O)C.O>[Cl:18][C:13]1[CH:14]=[C:15]([CH:16]=[CH2:17])[C:9]2[O:8][CH:7]([C:19]([F:21])([F:20])[F:22])[C:6]([C:4]([OH:5])=[O:3])=[CH:11][C:10]=2[CH:12]=1
Reactant: C=COC(=O)C1=Cc2cc(Cl)cc(C=C)c2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1cc(Cl)cc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
The ester (Step 1) (0.350 g, 1.05 mmol) was dissolved in a solution of THF:ethanol:water (7:2:1; 10 mL), was treated with sodium hydroxide (0.46 mL, 1.05 mmol of a 2.5 N solution), and stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was dissolved in water (10 mL). Diethyl ether (10 mL) was added and the mixture acidified with concentrated HCl. The layers were separated, and the aqueous phase was extracted with diethyl ether (2×10 mL). The organic phases were combined, dried over MgSO4, filtered, and evaporated to yield a yellow solid, which was recrystallized in diethyl ether-hexane to afford the title compound as a yellow solid (0.288 g, 90%): mp 183.2–185.8° C. 1H NMR (CDCl3/300 MHz) 7.77 (s, 1H), 7.49 (d, 1H, J=2.2 Hz), 7.16 (d, 1H, J=2.4 Hz), 6.93 (dd, 1H, J=11.3, 17.7 Hz), 5.82 (d, 1H, J=17.7 Hz), 5.74 (q, 1H, J=6.9 Hz), 5.43 (d, 1H, J=11.1 Hz). FABLRMS m/z 303 (M−H). ESHRMS m/z 303.0014 (M−H, Calc'd. 303.003582). Anal. Calc'd. for C13H8ClF3O3+1.58% H2O: C, 50.44; H, 2.78. Found: C, 50.42; H, 2.65.
Reaction SMILES: [CH3:1][C:2]1[C:15]([F:16])=[C:14]([F:17])[CH:13]=[C:12]([F:18])[C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:19]([O-])([O-])OCC.C(OC(=O)C)(=O)C.Cl.[NH2:33][C:34]1[CH:38]=[N:37][S:36][N:35]=1>>[S:36]1[N:37]=[CH:38][C:34]([NH:33][CH:19]=[C:6]([C:4](=[O:5])[C:3]2[C:12]([F:18])=[CH:13][C:14]([F:17])=[C:15]([F:16])[C:2]=2[CH3:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:35]1
Reactant: CCOC(=O)CC(=O)c1c(F)cc(F)c(F)c1C
Reactant: CCOC([O-])[O-]
Reactant: Nc1cnsn1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(=CNc1cnsn1)C(=O)c1c(F)cc(F)c(F)c1C

Procedure:
Compound No. 157 (colorless needles) was prepared in a similar manner to Example 17, proceeding from the corresponding compounds ethyl 2-methyl-3,4,6,-trifluorobenzoylacetate, ethyl orthoformate, acetic anhydride and 3-amino-1,2,5-thiadiazole hydrochloride.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[O:24]=[C:25]1[NH:30][C:29]2[CH:31]=[CH:32][CH:33]=[C:34]([C:35](O)=[O:36])[C:28]=2[O:27][CH2:26]1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:35]([C:34]2[C:28]3[O:27][CH2:26][C:25](=[O:24])[NH:30][C:29]=3[CH:31]=[CH:32][CH:33]=2)=[O:36])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: O=C1COc2c(cccc2C(=O)O)N1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3c2OCC(=O)N3)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxylic acid. LC-MS (basic): tR=0.77 min; [M+H]+=503.0.
Reaction SMILES: [CH3:1][C:2]1([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17](=[O:20])(=[O:19])[NH2:18])[CH:12]=2)=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:22]1[C:23]2[C:30]([CH3:31])=[CH:29][NH:28][C:24]=2[N:25]=[CH:26][N:27]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH3:1][C:2]1([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17](=[O:20])(=[O:19])[NH2:18])[CH:12]=2)=[O:9])[CH2:3][CH2:4][N:5]([C:22]2[C:23]3[C:30]([CH3:31])=[CH:29][NH:28][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:6][CH2:7]1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Reactant: CC1(C(=O)Nc2cccc(S(N)(=O)=O)c2)CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c[nH]c2ncnc(N3CCC(C)(C(=O)Nc4cccc(S(N)(=O)=O)c4)CC3)c12
Temperature: 105 °C
Yield: 21 %

Procedure:
4-Methyl-N-(3-sulfamoylphenyl)piperidine-4-carboxamide from step B (33 mg, 0.098 mmol), 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (16 mg, 0.098 mmol), N,N-diisopropylethylamine (51 mg, 0.39 mmol), and isopropanol (1.0 mL) were combined in a pressure rated sealed tube and heated at 105° C. for 18 hours. The mixture was concentrated, and the residue was purified by preparative HPLC to give the title compound in 21% yield.
Reaction SMILES: C[C:2]1[C:3]([CH3:30])=[C:4]([C:23](=[N:27][O:28][CH3:29])[C:24]([NH2:26])=[O:25])[CH:5]=[C:6]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[N:9]=2)[CH:7]=1.CN.[CH2:33](OCC)C>O1CCCC1>[CH3:29][O:28][N:27]=[C:23]([C:4]1[CH:5]=[C:6]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[N:9]=2)[CH:7]=[CH:2][C:3]=1[CH3:30])[C:24]([NH:26][CH3:33])=[O:25]
Reactant: CCOCC
Reactant: CON=C(C(N)=O)c1cc(-c2ccn(-c3cccc(C(F)(F)F)c3)n2)cc(C)c1C
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)C(=NOC)c1cc(-c2ccn(-c3cccc(C(F)(F)F)c3)n2)ccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl α-(methoxyimino)-2-methyl-5-[1-[3-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl]benzeneacetamide (i.e. the product of Example 13) (0.062 g, 0.149 mmol) in tetrahydrofuran (2 mL) under a nitrogen atmosphere was added methylamine (33% by weight in ethanol). The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure to leave a solid. Hexanes and diethyl ether were added to the solid, and the mixture was filtered to obtain the tile compound, a compound of the present invention, as a white solid (56 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][NH:12][CH:13]2[CH2:15][CH2:14]2)=[CH:8][CH:7]=1.CS[C:18](SC)=[CH:19][N+:20]([O-:22])=[O:21].[NH3:25]>>[CH:13]1([NH:12][CH2:11][C:9]2[O:10][C:6]([CH2:5][S:4][CH2:3][CH2:2][NH:1][C:18]([NH:25][CH2:2][CH2:3][S:4][CH2:5][C:6]3[O:10][C:9]([CH2:11][NH:12][CH:13]4[CH2:15][CH2:14]4)=[CH:8][CH:7]=3)=[CH:19][N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=2)[CH2:15][CH2:14]1
Reactant: N
Reactant: NCCSCc1ccc(CNC2CC2)o1
Reactant: CSC(=C[N+](=O)[O-])SC
Product: O=[N+]([O-])C=C(NCCSCc1ccc(CNC2CC2)o1)NCCSCc1ccc(CNC2CC2)o1

Procedure:
A mixture of 5-[[(2-aminoethyl)thio]methyl]-N-cyclopropyl-2-furanmethanamine (1.67 g) and 1,1-bis-(methylthio)-2-nitroethene (0.61 g) was heated at 98°-100° for 3hr. The oily residue was chromatograpged (silica/methanol-0.88 ammonia 79:1) and the appropriate eluate evaporated to dryness to give the title compound (1.07 g) as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=O)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].COCCO[AlH2-]OCCOC.[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccnc(C(=O)N2CCOCC2)c1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1ccnc(CN2CCOCC2)c1
Temperature: 90 °C
Yield: 31.5 %

Procedure:
A solution of 44 (1 g, 3.25 mmol) in toluene was heated to 50° C. and Red-Al (2.2 mL, 8.14 mmol) was introduced at 50° C. After the addition was complete, the reaction mixture was heated at 90° C. for 2 h. The reaction mixture was cooled to rt, basified with 1N aq. NaOH solution and extracted with 10% MeOH/CHCl3. The combined organic layer was dried over Na2SO4, concentrated and the obtained crude compound was purified by silica gel chromatography (100-200 mesh, eluted with 2% MeOH/DCM) to get compound 45 (300 mg, 33%) as gummy liquid; (m/z): 294 [MH]+; 1H NMR (400 MHz, DMSO-d6) δ 9.76 (1H, s), 8.24 (1H, d, J=5.6 Hz), 7.53 (1H, d, J=1.2 Hz), 7.30 (1H, d, J=2.0, 5.6 Hz), 3.58 (4H, t, J=4.6 Hz), 3.48 (2H, s), 2.40-2.38 (4H, m), 1.49 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:6].[NH2:20][C:21]1[N:26]=[C:25]([CH3:27])[CH:24]=[C:23]([Cl:28])[N:22]=1.Cl>C(OCCO)C.C(OCC)(=O)C>[ClH:28].[NH2:20][C:21]1[N:22]=[C:23]([NH:1][C:2]2[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=2)[C:5]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)=[O:6])[CH:24]=[C:25]([CH3:27])[N:26]=1
Reactant: Nc1cccc(C(=O)Nc2ccc([N+](=O)[O-])cc2)c1
Reactant: Cc1cc(Cl)nc(N)n1
Agent: Cl
Solvent: CCOCCO
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2cccc(C(=O)Nc3ccc([N+](=O)[O-])cc3)c2)nc(N)n1
Temperature: 20 °C
Yield: 98.2 %

Procedure:
3-Amino-N-(4-nitrophenyl)benzamide (B1) (1.0 g, 3.89 mmol) and 4-chloro-6-methyl-2-pyrimidinylamine (A8) (569 mg, 3.89 mmol) were dissolved in warm 2-ethoxyethanol. (20 mL). Two drops c.HCl was then added to the reaction mixture and refluxed for 1 h. by this time TLC and mass spec. showed completion of the reaction. The reaction mixture was diluted with ethyl acetate and cooled to 20° C. The resulting precipitate was filtered, washed with more EtOAc and recrystallized from MeOH/EtOAc/Charcoal/Celite to give B2 (1.531 g, 98%); m.p (MeOH/EtOAc)>300° C.; 1H NMR [(CD3)2SO] δ12.86 (br s, 1 H, N+H), 10.90 (s, 1 H, NH), 10.80 (br s, 1 H, NH), 8.30-8.26 (m, 2H, ArH), 8.11-8.08 (m, 4 H, ArH), 7.80-7.78 (br m, 3 H, ArH & NH2), 7.56 (t, J=7.8 Hz, 1 H, ArH), 2.30 (s, 3 H, CH3); mass APCI+ 365.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[O:20]([CH2:27][CH:28]1[NH:33][CH2:32][CH2:31][NH:30][CH2:29]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:30]4[CH2:31][CH2:32][NH:33][CH:28]([CH2:27][O:20][C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH2:29]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: c1ccc(OCC2CNCCN2)cc1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNC(COc4ccccc4)C3)c(F)cc2c1=O

Procedure:
A 0.6 g portion of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.23 g of 3-(phenoxymethyl)piperazine and 5 ml of pyridine were reacted as described in Example 81, giving 235 mg of the desired product, mp 112°-115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=1[C:35]([O:37][CH2:38][CH3:39])=[O:36]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH2:38]([O:37][C:35](=[O:36])[C:27]1[CH:28]=[C:29]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:9]([CH3:24])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=3)[C:11]([F:13])([F:14])[F:12])[CH:4]=2)[CH:30]=[CH:31][C:26]=1[Cl:25])[CH3:39]
Reactant: CCOC(=O)c1cc(B(O)O)ccc1Cl
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(Oc2ccc(Cl)c(C(C)C(O)(c3ccc(=O)n(C)c3)C(F)(F)F)c2)ccc1Cl

Procedure:
In analogy to Example 151, step 8, 5-[2-(2-chloro-5-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 189, step 5) was reacted with 4-chloro-3-ethoxycarbonylphenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a colorless foam. MS (m/e)=544.2 [M+H+].
Reaction SMILES: [C-:1]#[N:2].[Na+].CC1C=CC(S(O[CH2:15][C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])(=O)=O)=CC=1>CS(C)=O.S([O-])([O-])(=O)=O.[Fe+2]>[C:1]([CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])#[N:2]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: [C-]#N
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CC#N
Temperature: 90 °C
Reaction time: 5 h
Yield: 74.2 %

Procedure:
Sodium cyanide (8.2 g) was added to a solution of tert-butyl (S)-2-(4-methylbenzenesulfonyloxymethyl)pyrrolidine-1-carboxylate (Intermediate 140, 29.6 g) in DMSO (300 mL) and the resultant mixture was stirred and heated at 90° C. for 5.5 hours. After cooling, the mixture was treated with saturated aqueous iron (II) sulphate solution and the mixture was stirred for a further 5 hours then extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and petroleum ether (5%) to give tert-butyl (S)-2-cyanomethylpyrrolidine-1-carboxylate (13.0 g) as a light yellow oil which was used without further characterisation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([S:28][C:29]2[CH:38]=[C:37]([CH3:39])[C:32]3[NH:33][C:34](=[O:36])[O:35][C:31]=3[CH:30]=2)[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([S:28][C:29]5[CH:38]=[C:37]([CH3:39])[C:32]6[NH:33][C:34](=[O:36])[O:35][C:31]=6[CH:30]=5)[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: Cc1cc(Sc2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Sc4cc(C)c5[nH]c(=O)oc5c4)ncn3)CC1)C(=O)N2
Temperature: 130 °C
Reaction time: 2 h

Procedure:
187 mg (0.681 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 180 mg (0.490 mmol) 6-(6-chloro-pyrimidin-4-ylsulphanyl)-4-methyl-3H-benzoxazol-2-one and 200 mg (1.45 mmol) potassium carbonate were combined in 5.0 mL NMP and stirred for 2 h at 130° C. The reaction mixture was cooled overnight, filtered and the filtrate was purified by preparative HPLC. The product-containing fractions were combined, evaporated down and dried i. vac.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[I:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1.I[CH2:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1.CN1CCCN(C)C1=O>[CH:26]1([CH2:25][CH:20]([C:17]2[CH:16]=[CH:15][C:14]([I:13])=[CH:19][CH:18]=2)[C:21]([OH:23])=[O:22])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(O)Cc1ccc(I)cc1
Reactant: ICC1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: CC(C)NC(C)C
Product: O=C(O)C(CC1CCCC1)c1ccc(I)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
A solution of diisopropylamine (11.2 mL, 80.13 mmol) in tetrahydrofuran (120 mL) cooled to −78° C. was treated with a 2.5M solution of n-butyllithium in hexanes (32 mL, 80.13 mmol). This solution was stirred at −78° C. for 30 min and then treated with a solution of (4-iodo-phenyl)-acetic acid (9.67 g, 36.9 mmol) in tetrahydrofuran (88 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (29 mL). The reaction mixture was allowed to stir at −78° C. for 1 h. At this time, the reaction was treated with iodomethylcyclopentane (8.53 g, 40.6 mmol). The reaction mixture was allowed to slowly warm to 25° C. where it was stirred at 25° C. for 18 h. At this time, the reaction mixture was quenched with water (5 mL) and then concentrated in vacuo. The residue was diluted with water (800 mL) and then acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2×800 mL). The combined organic extracts were washed with water (1×600 mL) and a saturated aqueous sodium chloride solution (1×600 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (7.34 g, 57.8%) as a white solid: mp 105-107° C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].C(Cl)(=O)C1C=CC=CC=1.[CH3:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([CH3:40])[C:35]=1[O:36][CH2:37][O:38][CH3:39])[C:30](Cl)=[O:31]>>[CH2:10]([N:5]1[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:30](=[O:31])[C:29]2[CH:28]=[C:27]([CH3:26])[C:35]([O:36][CH2:37][O:38][CH3:39])=[C:34]([CH3:40])[CH:33]=2)[N:3]=[CH:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COCOc1c(C)cc(C(=O)Cl)cc1C
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Solvent: O=C(Cl)c1ccccc1
Product: COCOc1c(C)cc(C(=O)Nc2ncn(Cc3ccccc3)c2C(N)=O)cc1C

Procedure:
An amidation reaction and post-treatment were carried out according to the conditions of Example 1, using 1.06 g (4.9 mmol) 4-amino-1-benzyl-5-imidazolecarboxamide prepared in Reference Example 2 and, instead of benzoyl chloride, 3,5-dimethyl-4-methoxymethoxybenzoyl chloride which was separately prepared by a conventional method, to obtain 1.40 g of 1-benzyl-4-(3,5-dimethyl-4-methoxymethoxybenzoyl-amino)-5-imidazolecarboxamide.